Differences in the In Vivo and In Vitro Metabolism of Imrecoxib in Humans: Formation of the Rate-Limiting Aldehyde Intermediate
文献类型：期刊论文
| 作者 | Hou, Xiangyu1,2; Zhou, Jialan1; Yu, Songda1; Zhou, Lei1; Zhang, Yifan1 ; Zhong, Dafang1,2; Chen, Xiaoyan1,2
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| 刊名 | DRUG METABOLISM AND DISPOSITION
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| 出版日期 | 2018-09-01 |
| 卷号 | 46期号:9页码:1320-1328 |
| ISSN号 | 0090-9556 |
| DOI | 10.1124/dmd.118.081182 |
| 文献子类 | Article |
| 英文摘要 | Imrecoxib is a typical cyclooxygenase-2 inhibitor and the benzylic carbon motif is its major site of oxidative metabolism, producing a hydroxymethyl metabolite (M1) and a carboxylic acid metabolite (M2). The plasma exposure of M2 is four times higher than those of both M0 and M1 in humans. However, this metabolite is rarely formed in in vitro experiments. Therefore, this study aims to investigate the formation mechanism of M2 and to further elucidate the reason for the discrepancy between in vitro and in vivo metabolic data. By employing human hepatocytes, human liver microsomes (HLMs), human liver cytosols (HLCs), recombinant enzymes, and selective enzyme inhibitors, the metabolic map of imrecoxib was elaborated as follows: the parent drug was initially hydroxylated to form M1 in HLMs, mainly mediated by CYP3A4 and CYP2D6, and to subsequently formaldehyde imrecoxib (M-CHO) in HLMs and HLCs. The latter process is the rate-limiting step in generating the end-product M2. In further M-CHO metabolism, two opposite reactions (namely, rapid oxidation catalyzed by CYP3A4, CYP2D6, and cytosolic aldehyde oxidase to form M2 versus reduction to regenerate M1 mediated by NADPH-dependent reductases in HLMs and HLCs, such as cytochrome P450 reductase) led to marked underestimation of the M2 amount in static in vitro incubations. The findings provided a possible explanation for the difference between in vitro and in vivo metabolism of imrecoxib, suggesting that the effect of competitive reduction on the static oxidation metabolism in in vitro metabolic experiments should be considered. |
| WOS关键词 | HEALTHY MALE-VOLUNTEERS ; ALCOHOL-DEHYDROGENASE ; CYTOCHROMES P450 ; CYCLOOXYGENASE-2 INHIBITOR ; OXIDATIVE-METABOLISM ; LIVER ; EXCRETION ; CELECOXIB ; REDUCTASE ; ENZYMES |
| 资助项目 | National Natural Science Foundation of China[81573500] ; Strategic Priority Research Program of the Chinese Academy of Sciences[XDA 12050306] |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000444250400008 |
| 出版者 | AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/279596]  |
| 专题 | 上海药物代谢研究中心 |
| 通讯作者 | Chen, Xiaoyan |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, 501 Haike Rd, Shanghai 201203, Peoples R China; 2.Univ Chinese Acad Sci, Beijing, Peoples R China |
| 推荐引用方式 GB/T 7714 | Hou, Xiangyu,Zhou, Jialan,Yu, Songda,et al. Differences in the In Vivo and In Vitro Metabolism of Imrecoxib in Humans: Formation of the Rate-Limiting Aldehyde Intermediate[J]. DRUG METABOLISM AND DISPOSITION,2018,46(9):1320-1328. |
| APA | Hou, Xiangyu.,Zhou, Jialan.,Yu, Songda.,Zhou, Lei.,Zhang, Yifan.,...&Chen, Xiaoyan.(2018).Differences in the In Vivo and In Vitro Metabolism of Imrecoxib in Humans: Formation of the Rate-Limiting Aldehyde Intermediate.DRUG METABOLISM AND DISPOSITION,46(9),1320-1328. |
| MLA | Hou, Xiangyu,et al."Differences in the In Vivo and In Vitro Metabolism of Imrecoxib in Humans: Formation of the Rate-Limiting Aldehyde Intermediate".DRUG METABOLISM AND DISPOSITION 46.9(2018):1320-1328. |
入库方式： OAI收割
来源：上海药物研究所
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